Characterization of Selective Exosite-Binding Inhibitors of Matrix Metalloproteinase 13 That Prevent Articular Cartilage Degradation in Vitro [electronic resource]

• Ngôn ngữ: eng
• Ký hiệu phân loại: 562.7 Fossil invertebrates
• Thông tin xuất bản: Washington, D.C. : Oak Ridge, Tenn. : United States. Dept. of Energy. Office of Science ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2014
• Mô tả vật lý: Size: p. 9598-9611 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 261320
• Chủ đề: 1. 37 inorganic, organic, physical, and analytical chemistry; 2. 59 basic biological sciences; 3. 60 applied life sciences

Tóm tắt

 Matrix metalloproteinase 13 (MMP-13) has been shown to be the main collagenase responsible for degradation of articular cartilage during osteoarthritis and therefore represents a target for drug development. Here, as a result of high-throughput screening and structure$-$activity relationship studies, we identified a novel, highly selective class of MMP-13 inhibitors (compounds 1 (Q), 2 (Q1), and 3 (Q2)). Mechanistic characterization revealed a noncompetitive nature of these inhibitors with binding constants in the low micromolar range. Crystallographic analyses revealed two binding modes for compound 2 in the MMP-13 S<
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 ' subsite and in an S<
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 * subsite. Type II collagen- and cartilage-protective effects exhibited by compounds 1, 2, and 3 suggested that these compounds might be efficacious in future in vivo studies. Lastly, these compounds were also highly selective when tested against a panel of 30 proteases, which, in combination with a good CYP inhibition profile, suggested low off-target toxicity and drug$-$drug interactions in humans.